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C O M M E N TA R Y Use of HMG-CoA Reductase Inhibitors in the HIV Population: Implications for Individualized Treatment Selection Ashish Advani, PharmD; Manish Patel, PharmD, BCPS; Roberto V. Pichardo, PharmD; Yolanda Whitty, PharmD; and Shreena Advani, PharmD T he World Health Organization reports that 34 million people are living with human immunodeficiency virus (HIV) worldwide.1 Several global organizations are making concerted efforts to treat and prevent HIV, centered around providing antiretroviral therapy (ART) to those who are infected and those at risk for infection. The first antiretroviral (ARV), zidovudine, was approved in 1987. Zidovudine belongs to the subclass known as nucleoside reverse transcriptase inhibitors (NRTIs). Since the advent of zidovudine, additional NRTIs and numerous other classes of ARVs have been introduced to the market, including nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors, fusion inhibitors, and coreceptor inhibitors. The use of these various classes in combination, known as highly active ART (HAART), provided yet another breakthrough in HIV treatment. In 2008, the Antiretroviral Therapy Cohort Collaboration collected data from several developed countries that showed increased life expectancy for those who began HAART at a CD4+ cell count > 200 per microliter of blood.2 Although HAART benefits people living with HIV, ARVs are not without significant risks. For instance, PIs, a key component of HAART, are associated with insulin resistance, lipodystrophy, dyslipidemia, and hepatoxicity. Notably, it has been estimated that the prevalence of hyperlipidemia in patients receiving PI-based ART may be close to 80%. The Department of Health and Human Services (DHHS) guidelines recommend the use of at least 3 ARVs in combination; of the 4 preferred regimens for nonpregnant, treatment-naïve HIV patients, 2 contain PIs.3 Increased use of PIs and other ARVs, along with an increase in life expectancy, are suggested factors that explain a trend of increased hyperlipidemia diagnoses seen in the HIV-infected population. Statins are a class of medications used to block cholesterol production in the liver. While statins are generally deemed well tolerated, serious side effects such as lethal rhabdomyolysis can occur when concentrations are increased. Recently, a review of drug-drug interactions between statins and PIs, with an emphasis on metabolic pathways, was published. Of the 7 statins currently available (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin), 3 (atorvastatin, lovastatin, and simvastatin) are metabolized through cytochrome P450 (CYP) 3A. All PIs except nelfinavir are coadministered with ritonavir, which is considered a potent 262 Journal of Managed Care & Specialty Pharmacy JMCP March 2014 3A inhibitor. Therefore, concurrent use of PIs and statins can lead to decreased hepatic metabolism of statins and resultant increased serum statin concentration. Further, cobicistat, a new agent to be used in combination with various ARVs, is considered another potent CYP3A inhibitor.4 Drug interactions between statins and ARTs are not limited to PIs. Agents within the NNRTI class are also known to interact. In particular, efavirenz and etravirine have been noted to alter levels of certain statins. These agents are known inducers of CYP3A enzymes, so they have the capacity to increase metabolism of statins reliant on CYP3A4 for breakdown. The DHHS guidelines report a 68% decrease in simvastatin levels, up to a 43% decrease in atorvastatin levels, and a 44% decrease in pravastatin levels when administered with efarvirenz. The potential implication of this interaction is significant, since efavirenz is a component of a preferred ARV regimen for nonpregnant, treatment-naïve HIV patients. Additionally, efavirenz use has been associated with dyslipidemia. Other NNRTIs that are noted to have the potential for an interaction with statins include rilpivirine and nevirapine.3 This commentary offers a comprehensive collection of relevant clinical literature as well as analysis and discussion of the potential interaction between statins and treatments for HIV. After an overview of the HIV population and treatment, observational data regarding statin use are examined. Finally, implications are discussed in the context of personalized medication selection based on HIV population considerations. ■■ Overview of HIV Population and Use of Concomitant Medications HIV Comorbities HIV infection is associated with several chronic conditions, including cardiovascular disease (CVD), diabetes, renal disease, and bone disease. Deaths attributed to these non-AIDS (acquired immune deficiency syndrome)-related comorbidities in HIV-infected patients has increased over the past 15 years, and an increasing number of guidelines are recommending evaluation of risks for these conditions.5 The relative risk of developing CVD in HIV patients has been estimated to be 61% higher than in non-HIV patients.6 The manifestation of coronary atherosclerosis in HIV patients is hypothesized to be due to a higher prevalence of conventional risk factors (smoking, dyslipidemia, hypertension, and insulin abnormalities); emerging risk factors (chronic Vol. 20, No. 3 www.amcp.org Use of HMG-CoA Reductase Inhibitors in the HIV Population: Implications for Individualized Treatment Selection inflammation, immune activation, and HIV-related senescence); and the role of ART. These factors are suggested to play a crucial role in the increased risk of CVD in the HIV population.7 The effects of HIV infection and ART on surrogate markers of atherosclerosis and lipoprotein metabolism were evaluated in HIV-positive treated and nontreated male patients (N = 46). Participants were assigned to 1 of 3 study groups: treatmentnaïve (n = 19), treatment with an NNRTI-containing regimen (n = 18), or treatment with a PI-containing regimen (n = 9). Patients underwent assessment of surrogate markers of atherosclerosis and variables of lipoprotein metabolism at baseline and at 12 months.8 In the PI treatment group, total cholesterol (TC) rose from 4.4 ± 0.9 to 6.1 ± 1.6 millimole per liter (mmol/L; P < 0.05 vs. baseline) and triglycerides rose from 1.7 ± 1.0 to 2.5 ± 0.5 mmol/L (P < 0.05 vs. baseline), but no significant changes were seen in other study groups. Carotid intima thickness, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) did not significantly change from baseline in any study groups.8 A cross-sectional study evaluated the effects of HIV infection and ART on lipoprotein metabolism in HIV-positive treated and nontreated and HIV-negative Caucasian male patients (N = 86). Participants were assigned to 1 of 4 study groups: HIV-negative (n = 33), HIV-infected treatment naïve (n = 11), HIV-infected currently untreated (n = 14), or HIV-infected with PI treatment (n = 28).9 TC and LDL-C were significantly lower in the HIV-infected treatment-naïve group compared with each of the other 3 study groups. Triglycerides were significantly lower, and HDL-C was significantly higher in the HIV-negative group compared with each of the other 3 study groups.9 A retrospective cohort analysis compared the mean age at diagnosis, incidence rates (IR), and adjusted incidence rates (aIR) by HIV status for myocardial infarction (MI), end-stage renal disease (ESRD), and non-AIDS-defining cancer. The study population included patients from the Veterans Aging Cohort Study who were matched 1 HIV-positive to 2 HIVnegative by age, race, and clinical site from October 2003 to September 2008. Outcomes were measured by incident occurrences of MI, ESRD, and non-AIDS-defining cancer.10 The number of MI, IR, and aIR was 286 versus 231, 1.31 (95% confidence interval [CI] = 1.17-1.47) versus 2.18 (95% CI = 1.92-2.48), and 1.00 versus 1.81 (95% CI = 1.49-2.20) for the HIV-negative (n = 56,456) and HIV-positive (n = 27,988) groups, respectively.10 A Cox proportional hazards analysis was conducted to examine the association of cumulative exposure to any statin drug and mortality or onset of non-AIDS complications (CVD, malignancies, and fragility fractures) in patients infected with HIV on HAART. The study assessed 25,884 patients with HIV with HAART exposure of greater than 14 days with a median www.amcp.org Vol. 20, No. 3 follow-up time of 6.62 years. The association of cumulative exposure to any statin and occurrences of death, CVD, malignancies, and fragility fractures was assessed.11 Of the patients evaluated, 9,082 (35%) were prescribed statins. The total statin exposure was 26,487 patient years. The hazard ratios per year of statin exposure of death, CVD, malignancies, and fragility fractures were 0.96 (95% CI = 0.90-1.02), 1.02 (95% CI = 0.98-1.06), 0.96 (95% CI = 0.92-1.00), and 0.90 (95% CI = 0.81-1.01), respectively.11 In summary, CVD disease is a significant comorbidity factor in the HIV population. Increased triglycerides have been reported in HIV patients, especially those on protease inhibitors. HIV patients are also at increased risk for MI. Concomitant Medication Needs A cross-sectional analysis was conducted among patients within the HIV Outpatient Study (HOPS) cohort who were prescribed ARV therapy to characterize the extent of polypharmacy and its consequences in HIV-infected patients. The HOPS is an ongoing prospective observational cohort study of HIV-infected adults that has been collecting data since 1993. Patients selected for this analysis (N = 3,810) had to have a CD4 + T-lymphocyte count and HIV RNA viral load (VL) recorded within 6 months before or during the 5-year study period and had to have taken ARV therapy for > 2 weeks during the study period. The percentage of patients who were prescribed ≥ 1 ARV/non-ARV combination that was contraindicated or had moderate to high evidence of interaction was assessed within the 5-year study period.12 Lipid-lowering medications were used concomitantly within the study’s 5-year observation period in 10% of the population under 50 years of age (n = 2,498) and 22% of the population aged 50 years or greater (n = 1,312). Among the patients analyzed, 267 (7%) were prescribed at least 1 contraindicated ARV/non-ARV combination. The contraindicated combination of ARV and statin therapy (lovastatin or simvastatin) was seen in 50 out of 267 (19%) of these patients.12 A retrospective cohort study was performed to examine drug trends associated with the concomitant use of statins and PIs before new National Cholesterol Education Program (NCEP) II guidelines (January 1, 1996, through December 31, 2000) were published, and after the guidelines were published (January 1, 2001, through June 20, 2002). Adult patients who had at least 2 prescriptions filled for ARV therapy (N = 4,505) were categorized into 3 groups according to PI in combination with pravastatin or atorvastatin (recommended), fluvastatin or cerivastatin (alternative), and simvastatin or lovastatin (contraindicated). The incidence of PI use, overall combination PI and statin use, and contraindicated PI-statin use combination in the pre- and postguideline publication periods were recorded.13 March 2014 JMCP Journal of Managed Care & Specialty Pharmacy 263 Use of HMG-CoA Reductase Inhibitors in the HIV Population: Implications for Individualized Treatment Selection TABLE 1 TABLE 2 Prevalence of PI and Combined PI-Statin Use Before and After NCEP II Guidelines13 Preguidelines Postguidelines 4,505 4,196 2,893(64.2) 2,122(50.6) 100(3.5) 168(7.9) P Value Included in cohort, N Any PI use, n (%) < 0.001 Combined PI-statin < 0.001 use, n (%) 42(42.0) 35(20.8) < 0.001 Contraindicated combinations,a n (%) aContraindicated combinations=PI+simvastatin or lovastatin. NCEP = National Cholesterol Education Program; PI = protease inhibitor. A total of 5,392 people received prescriptions for ARV drugs during the study period. PI use decreased from 64.2% during the preguideline period to 50.6% during the postguideline period (P < 0.001).13 The results are summarized in Table 1. These 2 studies show that lipid-lowering agents are often prescribed in HIV patients, especially those over the age of 50. Consequently, national cholesterol guidelines are important to guide clinicians to prevent unintentional prescribing of contraindicated statins in patients receiving PI therapy. HIV and Cholesterol Treatment with PIs has been associated with hypercholesterolemia and hypertriglyceridemia in clinical trials.14 Ritonavir, a PI used to boost drug concentrations of other PIs, increased LDL-C by 16% and triglycerides by 26% after 2 weeks of therapy at a boosting dose of 100 milligrams (mg) twice daily in a study of healthy volunteers.15 Dyslipidemia has been demonstrated with other PIs, including newer agents such as tipranavir; however, dyslipidemia is not prominent with all PIs.14 Atazanavir and darunavir, when boosted with ritonavir, have demonstrated less dyslipidemia than the PI lopinavir at 48 weeks in clinical trials.16,17 When compared with PIs, NNRTIs have been associated with less dyslipidemia in clinical studies.15 However, a trial comparing use of the NNRTI efavirenz to atazanavir, a PI, reported significantly increased dyslipidemia with efavirenz.18 In a multicenter, randomized trial comparing efavirenz to the NNRTI nevirapine, efavirenz was shown to cause a 31.1% increase in TC and a 49% increase in triglycerides compared with a 26.9% and 20% increase for nevirapine, respectively.19 In general, NRTIs cause less dyslipidemia than both PIs and NNRTIs.14 However, in clinical trials, treatment with NRTI stavudine has been associated with larger increases in TC, LDL-C, and triglyercides than with tenofovir, an NNRTI.20,21 Newer agents that are not classified as PIs, NNRTIs, or NRTIs, such as raltegravir and maraviroc, are reported in clinical studies as being options that avoid dyslipidemia.14 264 Journal of Managed Care & Specialty Pharmacy JMCP March 2014 Overall Effects of Main ARV Drugs on Lipid Profiles in HIV-Infected Patients14 Total Antiretroviral Cholesterol PIs (boosted) Lopinavir hh Atazanavir h Fosamprenavir h Saquinavir hh Darunavir h Tipranavir hh NNRTIs Efavirenz h Nevirapine h NRTIs Tenofovir n/h Abacavir n/h Lamivudine n Zidovudine h Stavudine hh CCR5 inhibitors Maraviroc n Integrase inhibitors Raltegravir n/h LDL-C HDL-C TGs hh n/h h hh h hh n/i n/i n/i n/i n/i n/i hhh n hh h h hhh h h h hh h n/h n/h h n h hh n/h h n h h n/h h n hh hh n n/h n n/h n/h n Note: hhh = very large increase; hh = moderate increase; h = small increase; n = no change; n/h = no change or small increase; n/i = no change or small decrease. ARV = antiretroviral; CCR5 inhibitors = CC chemokine receptor 5 entry inhibitors; HDL-C = high-density lipoprotein cholesterol; HIV = human immunodeficiency virus; LDL-C = low-density lipoprotein; NNRTIs = nonnucleoside reverse transcriptase inhibitors; NRTIs = nucleoside analog reverse transcriptase inhibitors; PIs = protease inhibitors; TGs = triglycerides. Finally, the effects on lipids attributed to enfuvirtide and the newer antiretrovirals—rilpivirine, etravirine, elvitegravir/cobicistat and dolutegravir—have also been evaluated. Compared with efavirenz, rilpivirine led to minimal changes in LDL-C, HDL-C, TC, and triglycerides in 2 recently reported trials.22,23 Similar observations were reported when etravirine was compared with efavirenz in the Study of Etravirine Neuropsychiatric Symptoms Versus Efavirenz Trial.24 In the etravirine group, TC, HDL-C, and LDL-C increased by 0.40 mmol/L, 0.10 mmol/L, and 0.20 mmol/L, respectively. In the efavirenz group, TC, HDL-C, and LDL-C increased by 1.0 mmol/L, 0.30 mmol/L, and 0.60 mmol/L, respectively. In univariate analyses, increases in TC, HDL-C, and LDL-C were all significantly greater in the efavirenz group as compared with the etravirine group.25 In another study, elvitegravir/cobicistat (EVG/COBI) was compared with efavirenz. In the EVG/COBI group, TC, HDL-C, and LDL-C increased by 0.25 mmol/L, 0.13 mmol/L, and 0.26 mmol/L, respectively. In the efavirenz group, TC, HDL-C, and LDL-C increased by 0.49 mmol/L, 0.20 mmol/L, and 0.44 mmol/L, respectively.26 Similar to elvitegravir, dolutegravir has minimal effects on lipids. In the Vol. 20, No. 3 www.amcp.org Use of HMG-CoA Reductase Inhibitors in the HIV Population: Implications for Individualized Treatment Selection TABLE 3 Statin Pharmacokinetics Lovastatin57 CYP3A4 Simvastatin58 Pravastatin59 Fluvastatin60 a CYP3A4 No CYP CYP2C9 (75%), CYP2C8 (~5%), CYP3A4 (~20%); saturable first-pass metabolism Rosuvastatin62 Pitavastatin63 Metabolism CYP2C9 and Primary: Hepatic CYP2C19 glucuronidation (UGT1A3 and UGT2B7); minimal CYP2C9 and, to a lesser extent, CYP2C8 Bioavailability < 5% < 5% 17% 24% Parent drug: 14% 20%; higher 51%; Cmax and AUC lower in blacks systemic active; in Asians than whites metabolite: 30% Lipophilic Yes Yes No Yes Yes No Yes Protein binding > 95% 95-98% ~50% 98% 96% 88% 99% Active metabolites Yes Yes No No Yes Yes No Elimination 3 hours 2 hours 1.8 hours 1.2 hours 7 to 14 hours; 19 hours 12 hours half-life metabolites: 20 to 30 hours Onset of action 3 days > 3 days Several days 4 weeks 3 to 5 days; 1 week; NA max: 2 weeks max: 4 weeks Time to peak 2 to 4 hours 1.3 to 2.4 hours 1 to 1.5 hours 1 hour 1 to 2 hours 3 to 5 hours 1 hour Excretion Feces (~83%); Feces (60%); Feces (70%); Feces (90%); NA Feces (90%) Feces (79%); urine (10%) urine (13%) urine (20%) urine (5%) urine (15%) a Pravastatin is not a CYP enzyme substrate, is in active drug form, and has no active metabolites formed via pharmacokinetic processes.30 AUC = area under the curve; Cmax = maximal concentration; CYP = cytochrome family of enzymes; NA = information not available. SPRING-2 trial, dolutegravir raised TC, HDL-C, LDL-C, and TG by 0.17 mmol/L, 0.07 mmol/L, 0.07 mmol/L, and 0.09 mmol/L, respectively.27 Finally, a substudy that prospectively pooled data from the T-20 Versus Optimized Background Regimen Only trials for 48 weeks evaluated the metabolic effects of enfuvirtide. Optimized background (OB) was defined as 3 to 5 ARVs prescribed based on treatment history and genotypic and phenotypic resistance data. In the enfuvirtide + OB group, TC, HDL-C, LDL-C, and triglycerides increased by 0.6 (95% CI = 0.37-0.78) mmol/L, 0.11 (95% CI = 0.08-0.13) mmol/L, 0.28 (95% CI = 0.15-0.40) mmol/L, and 0.48 (95% CI = -0.16-1.11) mmol/L, respectively. In the OB only group, TC, HDL-C, LDL-C, and triglycerides increased by 0.9 (95% CI = 0.53-1.34) mmol/L, 0.15 (95% CI = 0.08-0.21) mmol/L, 0.31 (95% CI = -0.02-0.64) mmol/L, and 0.78 (95% CI = 0.01.56) mmol/L, respectively. The authors concluded that the addition of enfuvirtide to an OB regimen did not appear to have unfavorable effects on metabolic parameters.28 A summary of the effects of HIV medications on cholesterol and triglycerides is presented in Table 2. ■■ Statin Use in the HIV Population Metabolism of Statins Most of the statins undergo significant metabolism via 1 or more of the CYP450 enzymes located in the gastrointestinal tract and liver, but some have minor or no metabolism via the CYP450 system. The pharmacokinetic parameters of statins available in the United States are summarized in Table 3. Lovastatin, simvastatin, and, to a lesser extent, atorvastatin undergo significant metabolism via CYP3A4 isozymes. www.amcp.org Vol. 20, No. 3 Atorvastatin61 CYP3A4 Pravastatin depends on glucuronidation for metabolism, has minimal interaction with the CYP450 system, and is excreted in an unchanged form. Fluvastatin is metabolized predominantly by CYP2C9 isozymes. Rosuvastatin undergoes minimal metabolism via CYP450 (CYP2C9 and CYP219) and is primarily excreted in a nonmetabolized form in the feces. Pitavastatin undergoes metabolism predominantly through glucuronidation (UGT1A3 and UGT2B7), with some minor metabolism via CYP2C9 and CYP2C8. An understanding of the metabolic pathways of statins may help predict potential drug-drug interactions between statins and drugs that inhibit or induce CYP450 enzymes, including ARVs. Potential Drug Interactions with ART The PIs, the NNRTI delavirdine, and cobicistat inhibit the CYP3A4 enzymes and thus have the potential to significantly increase statin levels. No significant interactions occur between statin drugs and nucleoside (or nucleotide) reverse transcriptase inhibitors raltegravir, enfuvirtide, or maraviroc. Nevirapine and efavirenz have the potential to induce CYP3A4 and thus reduce the level of statin drugs that are metabolized via CYP3A4. Although efavirenz is a mixed inhibitor and inducer of CYP3A4, it primarily induces metabolism of CYP3A4 substrates. Co-administration of efavirenz (600 mg) with either simvastatin (40 mg once daily), atorvastatin (10 mg once daily), or pravastatin (40 mg once daily) resulted in significant reductions in the area under the curve (AUC) at 0 to 24 hours for all 3 statins: 58% reduction for simvastatin, 43% for atorvastatin, and 40% for pravastatin.29 A separate study found that patients on an efavirenz-based ARV regimen who March 2014 JMCP Journal of Managed Care & Specialty Pharmacy 265 Use of HMG-CoA Reductase Inhibitors in the HIV Population: Implications for Individualized Treatment Selection TABLE 4 Statin Crestor (rosuvastatin) Severity of Clinically Significant Drug Interactions Between Statins and PIs Reported64 PI Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir/ritonavir Nelfinavir Saquinavir Tipranavir Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir/ritonavir Nelfinavir Saquinavir Tipranavir All PIs Risk Categorya D D D D D D D D D D D D D D D X NA Level of Documentation Good Fair Fair Fair Excellent Fair Fair Fair Fair Excellent Excellent Fair Excellent Fair Good Excellent NA Recommendation/Clinical Management • Initiate lowest possible rosuvastatin dose of 5 mg/day not to exceed 10 mg/day when combined with atazanavir or lopinavir/ritonavir. • Monitor for statin toxicity. • Evaluate benefit/risk ratio. • Titrate atorvastatin dose and use lowest clinically effective dose, not to exceed 20 mg daily. • Monitor for RhM, during initial months of therapy and titrations upward of the statin or PI. Lipitor • Consider periodic creatine phosphokinase level monitoring. (atorvastatin) • If RhM is diagnosed or suspected, temporarily withhold or discontinue atorvastatin. • Consider using other statins such as pravastatin or fluvastatin. • Avoid this combination. Lescol (fluvastatin) • No interactions of risk category A or greater identified. • Monitor clinical response to pitavastatin closely, including lipid Atazanavir C Fair Livalo response and signs and symptoms of muscle and liver toxicity. (pitavastatin) Lopinavir/ritonavir B Fair • No action needed. Mevacor (lovastatin) All PIs X Fair • Avoid this combination. Darunavir C Fair • Monitor for signs and symptoms of pravastatin toxicity. • Monitor for increased effects of Pgp substrates such as pravastatin Lopinavir/ritonavir C Fair since lopinavir/ritonavir is a Pgp inhibitor. Pravachol Nelfinavir C Good • Monitor for reduced pravastatin pharmacological effects/increased (pravastatin) dose requirements. Saquinavir C Good • Monitor for increased effects of Pgp substrates such as pravastatin, Tipranavir C Fair since tipranavir is a Pgp inhibitor. Zocor (simvastatin) All PIs X Fair-Good • Avoid this combination. a Risk categories: X = avoid combination; D = consider therapy modification; C = monitor therapy; B = no action needed. mg/day = milligrams per day; NA = not applicable; Pgp = P-glycoprotein; PI = protease inhibitor; RhM = rhabdomyolysis. received simvastatin (20 mg once daily) had good but not optimal decreases in LDL-C levels and no major adverse effects.30 Etravirine is an inducer of CYP3A, but an inhibitor of CYP2C9, CYP2C19, and P-glycoprotein. Efavirenz, nevirapine, and etravirine have the potential to decrease plasma concentrations of statins and thus lead to a reduced lipid-lowering response. Rilpivirine is not likely to cause significant alterations in the levels of statins. Delavirdine inhibits CYP3A4, but this ARV medication is rarely used.31 All PIs are metabolized by the enzyme CYP3A4, and all inhibit CYP3A4 to some degree. Accordingly, all PIs can increase the plasma concentration of the statin drugs that also undergo metabolism via CYP3A4. The degree of PI inhibition of CYP3A4 varies, with the greatest effect caused by ritonavir-boosted PI combinations.31 Simvastatin and lovastatin are contraindicated with all PIs and elvitegravir/cobicistat because of the potential for significant elevations in statin drug concentration and risk of toxicity.3 Both lopinavir/ritonavir and atazanavir/ritonavir may significantly 266 Journal of Managed Care & Specialty Pharmacy JMCP March 2014 increase plasma concentrations of rosuvastatin. Because of this, the U.S. Food and Drug Administration (FDA) recommends not exceeding rosuvastatin doses greater than 10 mg once daily when used in conjunction with either lopinavir/ritonavir or atazanvir/ritonavir. Similarly, atorvastatin plasma concentration may increase when given with PIs. The FDA recommends not exceeding an atorvastatin dose of 20 mg daily when prescribed with darunavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir, or fosamprenavir alone. Atorvastatin doses should not exceed 40 mg daily when given with nelfinavir and should be avoided altogether when given with tipranavir/ritonavir. For patients on lopinavir/ritonavir, atorvastatin should be cautiously used at the lowest atorvastatin dose necessary. Neither pravastatin nor pitavastatin are expected to be affected significantly by PIs. No dose limitations are recommended with either of these medications when prescribed with lopinavir/ritonavir or darunavir/ ritonavir. Also, no dose limitation is recommended when pitavastatin is given with atazanavir/ritonavir.32 Limited Vol. 20, No. 3 www.amcp.org Use of HMG-CoA Reductase Inhibitors in the HIV Population: Implications for Individualized Treatment Selection interaction data is available for fluvastatin; however, given its inferior anticholesterol activity, this particular statin is infrequently used in the clinical setting. The major reported drug interactions between statins and PIs are summarized in Table 4. Efficacy Studies of Statins in HIV Patient Population A pharmacokinetic/pharmacodynamic study based in the Netherlands evaluated the effects of concomitant use of rosuvastatin and lopinavir/ritonavir in HIV-infected patients (N = 22). Patients aged a mean of 48 years and taking lopinavir/ ritonavir with a TC > 239 milligrams per deciliter (mg/dL) were treated with rosuvastatin 10-40 mg for 12 weeks. The primary outcome was a mean percentage decrease in TC and LDL-C at weeks 4, 8, and 12.33 At baseline, week 4, week 8, and week 12, TC was 7.1 ± 0.95, 5.2 ± 0.81, 4.9 ± 1.20, and 4.7 ± 0.79, respectively; LDL-C was 4.2 ± 0.99, 2.8 ± 0.61, 2.7 ± 0.77, and 2.5 ± 0.61, respectively (in mmol/L). Reported adverse events included diarrhea (n = 2), headache (n = 2), and an upper respiratory tract infection (n = 2). Three patients experienced transient muscle pain/ cramps, and 3 patients had clinically asymptomatic creatine kinase increases greater than 250 units per liter (U/L), ranging from 363 to 676 U/L. Lopinavir and ritonavir concentrations were not significantly altered.33 A retrospective cohort study was conducted to compare the effectiveness and toxicity of statins among HIV-infected patients who started a statin between January 1, 2000, and March 1, 2008 (N = 700). The 3 most common statins prescribed were atorvastatin, mean dose 20 mg daily (n = 303); pravastatin, mean dose 40 mg daily (n = 280); and rosuvastatin, mean dose 10 mg daily (n = 95). Other statins were prescribed for 22 patients, but results were not included in the analysis. Toxicity was based on laboratory abnormalities and symptomatic complaints such as myalgias, gastrointestintal symptoms, and fatigue. The primary outcome measured was the change in lipid levels during statin therapy after 12 months.34 The median follow-up time was 19 months. TC was lowered by 39 (95% CI = 31-48) mg/dL in the atorvastatin group, 25 (95% CI = 16-34) mg/dL in the pravastatin group, and 43 (95% CI = 31-55) mg/dL in the rosuvastatin group. LDL-C was lowered by 26 (95% CI = 20-32) mg/dL in the atorvastatin group, 12 (95% CI = 5-19) mg/dL in the pravastatin group, and 23 (95% CI = 14-32) mg/dL in the rosuvastatin group. Statin toxicity was reported in 7.3% of patients on atorvastatin, 6.1% of patients on pravastatin, and 5.3% of patients on rosuvastatin. An elevation in creatine phosphokinase was the most common potentially serious toxicity followed by elevation in liver enzymes. Symptomatic adverse events were experienced by 29 patients, including myalgias/arthralgias (62%), gastrointestinal symptoms (21%), and fatigue (7%).34 www.amcp.org Vol. 20, No. 3 A phase 4, multicenter, 12-week, randomized, double-blind, double-dummy study evaluated the use of pitavastatin 4 mg and pravastatin 40 mg on LDL-C reduction after 12 weeks of therapy in HIV-infected adults on stable ART (N = 252) with dyslipidemia. The primary outcome measure was the percent change in fasting serum LDL-C from baseline to week 12.35 TC was lowered by 20.4% in the pitavastatin group, compared with 13.8% in the pravastatin group (P < 0.001). LDL-C was lowered by 35.1% in the pitavastatin group, compared with 20.9% in the pravastatin group (P < 0.001). Treatment-emergent adverse events caused 6 patients in the pitavastatin group and 5 patients in the pravastatin group to discontinue treatment. Reported adverse events in the pitavastatin arm included arthralgia (n = 3), myalgia (n = 1), back pain (n = 1), and pain in an extremity (n = 2). Adverse events in the pravastatin arm included arthralgia (n = 4), myalgia (n = 3), back pain (n = 2), and pain in an extremity (n = 3).35 A randomized, multicenter, open-label trial was conducted to compare the efficacy of rosuvastatin 10 mg and pravastatin 40 mg, after 45 days treatment, on plasma lipid levels in 88 HIV-1-infected patients taking a combined ART regimen containing at least 1 PI boosted with ritonavir. The primary outcome measure was the change in LDL-C.36 Median change in TC was -14% in the pravastatin group compared with -28% in the rosuvastatin group (P < 0.001). Median change in LDL-C was -19% in the pravastatin group compared with -37% in the rosuvastatin group (P < 0.001).36 An open-label, randomized, prospective, monocentric study assessed the safety and efficacy of rosuvastatin, pravastatin, and atorvastatin in the management of PI-associated hypercholesterolemia. Ninety-four patients with hypercholesterolemia on a stable PI regimen were assigned rosuvastatin 10 mg daily, pravastatin 20 mg daily, or atorvastatin 10 mg daily for 12 months. The primary endpoint was the decrease in TC and LDL-C levels relative to baseline.37 The overall decrease in TC was 25.2% in the rosuvastatin group, 17.6% in the pravastatin group (P = 0.01), and 19.8% in the atorvastatin group (P = 0.03). The reduction in LDL-C level was 26.3% in the rosuvastatin group, 18.1% in the pravastatin group (P = 0.04), and 20.3% in the atorvastatin group (P = 0.02). The most common adverse event seen was persistent gastrointestinal symptoms: 2 patients in the rosuvastatin group, 1 in the pravastatin group, and 2 in the atorvastatin group. No serious adverse events were reported.37 In summary, pravastatin, rosuvastatin, and atovorvastatin are commonly prescribed to manage hyperlipidemia in HIV patients. Among these 3 agents, rosuvastatin has the greatest cholesterol-lowering activity in this population. ■■ Personalized Medication Selection Based on HIV Population Considerations According to the Guidelines for the Evaluation and Management of Dyslipidemia in HIV-Infected Adults Receiving Antiretroviral March 2014 JMCP Journal of Managed Care & Specialty Pharmacy 267 Use of HMG-CoA Reductase Inhibitors in the HIV Population: Implications for Individualized Treatment Selection Therapy, drug intervention for elevated lipids in HIV patients is recommended if lifestyle and diet changes have not shown to be effective. The guidelines recommend patients be evaluated in accordance with NCEP Adult Treatment Panel (NCEP-ATP) III guidelines for dyslipidemia (however, NCEP-ATP III guidelines do not specifically address HIV-infected patients). For HIV patients with elevated LDL-C (or elevated non-HDL-C if triglycerides are between 200-500 mg/dL), pravastatin or atorvastatin therapy is recommended, with fluvastatin considered a safe alternative. If triglyceride levels are elevated above 500 mg/dL, then fibrate therapy with gemfibrozil or fenofibrate is recommended.38 However, in December 2011, the FDA issued a statement that the concomitant use of gemfibrozil and simvastin is contraindicated.39 When determining whether pharmacological therapy is appropriate, a cardiovascular risk assessment of the patient is advised per NCEP-ATP III guidelines using the following steps:40 1.Identify clinical atherosclerotic disease: (a) coronary heart disease (CHD), (b) MI, (c) unstable angina, (d) coronary angioplasty, or (e) stent. 2. Identify CHD risk equivalents: • Peripheral artery disease • Abdominal aortic aneurysm • Symptomatic carotid artery disease • Carotid stenosis > 50% • Stroke or transient ischemic attack • Diabetes 3. Count the number of risk factors summarized in Table 5 (in patients without clinical CHD or equivalents). 4. If there are ≥ 2 risk factors, determine the 10-year risk with Framingham scoring, using: • Age • TC • HDL-C • Blood pressure • Cigarette smoking status Considering the findings gathered from the risk assessment, recommendation for pharmacological therapy initiation is summarized in Table 6. The FDA has provided safety warnings regarding interactions between certain PIs and statin drugs that can increase the risk of muscle injury and has subsequently required the labels of both the PIs and affected statins (lovastatin, rosuvastatin, simvastatin, and atorvastatin) to be updated.32 Cost-Effectiveness Considerations The determinants of statin cost-effectiveness are based on the relationship between effectiveness and total cost of care among statins. A small cost-effectiveness ratio can be achieved by decreasing cost or increasing effectiveness of the statin. Statin effectiveness increases with increased dosage or by using the 268 Journal of Managed Care & Specialty Pharmacy JMCP March 2014 TABLE 5 NCEP-ATP III LDL-C Goal Modifying Risk Factors (Exclusive of LDL-C)40 Positive Risk Factors Cigarette smoking Hypertension HDL-C < 40 (mg/dL) Family history of premature CHD (male < 55; female < 45) Age (men ≥ 45; women ≥ 55) Negative Risk Factors (Subtract 1 Positive Risk Factor) HDL-C > 60 (mg/dL) CHD = coronary heart disease; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; mg/dL = milligrams per deciliter; NCEP-ATP = National Cholesterol Education Program Adult Treatment Panel. same dose of another statin with greater efficacy. The primary measure of statin effectiveness is survival, which can be measured as the number of life-years saved. Costs include drug costs, dose titration (including the cost of the office visit and laboratory tests), medical treatment for CHD, and all other long-term medical costs. The incremental cost-effectiveness ratio of a statin is lower in a high-risk population because the number of coronary events avoided is greater. Therefore, the recommendation is to use statins with the greatest effectiveness in high-risk patients and a less expensive statin in low-risk patients who require less LDL-C lowering.41 ■■ Discussion HIV Treatment Implications CVD is the leading cause of death for people living in the United States.42 In the era of HAART, CVDs are among the most important non-AIDS-related causes of morbidity and mortality in infected patients. The prevalence of CVD is expected to increase as HIV-infected patients live longer as a result of HAART. Recent projections estimate that by 2015, more than half of the HIV-positive population in the United States will be aged 50 years and older.43 HIV-associated dyslipidemia represents a clinically significant risk factor for cardiovascular disease. The most pronounced effect on triglyceride levels occurs with fulldose ritonavir; somewhat reduced effects are associated with ritonavir-boosted PIs; and a neutral effect is noted with unboosted atazanavir.44 Among “older” PIs, statistically significant elevations of triglyceride levels are observed with ritonavir and lopinavir/ritonavir.16,38,45 Compared with lopinavir/ ritonavir, boosted darunavir has been shown to induce less dyslipidemia.46 Among NNRTIs, efavirenz has been associated with dyslipidemia.18,19 It is important for clinicians to recognize the differing extent of cholesterol abnormalities observed among individual PIs and NNRTIs. These differences become important when selecting specific ARV regimens for individual patients, especially those with risk factors for CHD. Until recently, lopinavir/ritonavir-based HAART therapy was Vol. 20, No. 3 www.amcp.org Use of HMG-CoA Reductase Inhibitors in the HIV Population: Implications for Individualized Treatment Selection TABLE 6 NCEP-ATP III LDL-C Goal Modifying Risk Categories40 Risk Category Category Level LDL-C Goal (mg/dL) LDL-C Level to Initiate Drug Therapy ≥ 190, optional 160 to 189 0 to 1 risk factor Low to moderate < 160a ≥ 160 ≥ 2 risk factors + risk score < 10% Moderate < 130a ≥ 130 ≥ 2 risk factors + risk score 10-20% Next highest < 130a ≥ 130, optional 100 to 129 CHD or risk equivalents or risk score > 20% High or very high < 100a or < 70 a Initiate lifestyle changes when LDL-C is greater than LDL-C goal. CHD = coronary heart disease; LDL-C = low-density lipoprotein cholesterol; mg/dL = milligrams per deciliter; NCEP-ATP = National Cholesterol Education Program Adult Treatment Panel. recognized as first-line treatment for nonpregnant HIV-infected ARV-naïve patients. Efavirenz-based HAART therapy continues to be considered first line since 1998.3,47 Consequently, many HIV-infected individuals have been initiated on these specific therapies. Because of the high percentage of virologic and immunologic success, patients and clinicians are often reluctant to switch to alternate lipid neutral ARV regimens. Because of this, treating dyslipidemia to reduce CHD is common in the HIV population, especially as infected individuals grow older. Dyslipidemia in the HIV population is managed in accordance with the same guidelines established for the general population, namely the NCEP ATP III guidelines.38 Given the prevalence of lipid abnormalities among HIVinfected patients, statins have become one of the most prescribed drug classes in HIV care. Statin therapy is very effective in lowering LDL-C and non-HDL-C levels. Depending on the agent, they also moderately reduce triglyceride levels.48,49 Among HIV-infected patients, atorvastatin and rosuvastatin are associated with statistically significantly greater decreases in TC, LDL-C and non-HDL-C than pravastatin. The likelihood of reaching NCEP goals for LDL-C levels is higher with the use of rosuvastatin (odds ratio [OR], 2.1; P = 0.03) and atorvastatin (OR, 2.1; P = 0.001) compared with pravastatin.34 In another trial, patients taking atorvastatin or rosuvastatin had a greater reduction in triglycerides (26.8% and 26.1%, respectively) than those taking simvastatin or pravastatin (14.8% and 13.2%, respectively) for the 40 mg dose of each drug.49 A recent study reports superior reduction in LDL-C with pitavastatin 4 mg daily compared with pravastatin 40 mg daily (31.1% vs. 20.9%, respectively, P < 0.001) in HIV-infected adults. The investigators noted pitavastatin was associated with significantly greater reductions in Apolipoprotein B and TC compared with pravastatin 40 mg, but changes in triglycerides and HDL-C were not significantly different between treatments. There were no significant differences between pitavastatin 4 mg and pravastatin 40 mg in HIV-1 RNA VL or CD4+ cell counts. The overall adverse event profiles of pitavastatin 4 mg and pravastatin 40 mg appeared similar.35 PIs, NNRTIs (except rilpivirine), and cobicistat are known to inhibit and/or induce CYP450 iso-enzymes.3,50-52 Depending on the specific combination of statin drug and antiretroviral, a harmful drug-drug interaction may occur. Out of this concern, www.amcp.org Vol. 20, No. 3 clinicians must be attentive to the specific statin drug recommended when treating dyslipidemia in the HIV population. Pravastatin, low-dose atorvastatin, and low-dose rosuvastatin are commonly prescribed in HIV patients concurrently on a PI-containing regimen. In healthy volunteers, administration of pitavastatin 4 mg daily in the presence of steady state lopinavir/ritonavir 400/100 mg twice daily or darunavir/ritonavir 800/100 mg once daily did not result in clinically significant changes in pharmacokinetic exposures of either drug.53,54 In contrast, simvastatin and lovastatin are contraindicated for individuals on HIV PIs or cobicistat because of the potential for significant elevation in statin blood concentrations and increased risk for toxicity.35,49 Co-administration of the NNRTI efavirenz with simvastatin, atorvastatin, or pravastatin can result in significant induction of statin metabolism.55 The reduced inhibition of HMG-CoA reductase activity during co-administration of efavirenz may result in diminished antilipid efficacy at usual doses, and statin dosages may need to be cautiously increased. Unlike PIs, NNRTIs, and cobicistat, raltegravir has no inhibitory or inductive potential in vitro.56 Thus, clinically relevant drug interactions between raltegravir and statins are unexpected. Management of dyslipidemia to reduce CHD risk in HIVinfected patients is important. After lifestyle interventions, drug therapy with statins may be required. Clinicians should consider potency, toxicity, and potential for drug-drug interactions when choosing a statin drug for patients on ART. Managed Care Implications With the continual growth of managed care in the United States, financial and quality goals must be considered and equally balanced when selecting statin therapy. Many quality measures focus on numerical goals as defined by the Healthcare Effectiveness Data and Informational Set (HEDIS) and the Physician Quality Reporting System. Because Medicare 5-Star Quality Ratings are composed of HEDIS measures, Medicare Advantage health plans increasingly need to improve quality metrics. In many cases, appropriate medication use is the quickest and easiest method to attain quality goals. HEDIS cholesterol targets are met when LDL-C < 100 mg/dL is achieved in patients with coronary artery disease or diabetes and are best achieved by the use of statins. March 2014 JMCP Journal of Managed Care & Specialty Pharmacy 269 Use of HMG-CoA Reductase Inhibitors in the HIV Population: Implications for Individualized Treatment Selection Dyslipidemia is highly prevalent in patients with chronic HIV infection, subsequently increasing the risk of coronary artery disease in this patient population. ARV therapies consist of numerous agents with varying effects on lipids. In addition, drug interactions between statins and ARV therapies may lead to decreased efficacy or potential for increased toxicity. Many of the PIs used by HIV patients inhibit CYP3A4, raising the concentration of many of the commonly used statins. As a result, the choice of statin therapy should be carefully evaluated for HIV-positive patients with dyslipidemia. Optimal dyslipidemia therapy in this patient subgroup should begin with a statin that does not primarily depend on CYP3A4 for its metabolism. In the managed care sector, generic pravastatin would be a reasonable choice with the lower potential for CYP mediated drug-drug interactions. In addition, because of recent data in the HIV population and its largely non-CYP3A4-based metabolism, pitavastatin could also serve as a suitable alternative in the HIV positive subgroup of patients. The risk and benefit of statin therapy should be considered on an individualized patient basis. Subsequently, each managed care plan needs to evaluate statin therapy and access of specific statins for HIV-positive patients based on their specific membership make-up. Authors ASHISH ADVANI, PharmD, is Clinical Assistant Professor, Mercer University College of Pharmacy, Atlanta, Georgia. MANISH PATEL, PharmD, BCPS, is Clinical Pharmacist Specialist, and SHREENA ADVANI, PharmD, is Pharmacy Resident, Grady Health Systems, Atlanta, Georgia. ROBERTO V. PICHARDO, PharmD, is Pharmacy Director, Coventry Healthcare, Sunrise, Florida, and YOLANDA WHITTY, PharmD, is Pharmacy Resident, Atlanta Medical Center, Atlanta, Georgia. AUTHOR CORRESPONDENCE: Ashish Advani, PharmD, Clinical Assistant Professor, Mercer University College of Pharmacy and Health Sciences, 3001 Mercer University Dr., Atlanta, GA 30341. Tel.: 678.547.6223; Fax: 678.547.6384; E-mail: [email protected]. DISCLOSURES Funding was provided by Kowa Pharmaceuticals America, Inc., to support travel for a poster presentation at a national meeting. Authors attest to full access to all data and accountability for study findings and reporting. There has been no outside influence upon study design, data acquisition, interpretation of data, writing and revising the manuscript, and the decision to approve the final manuscript for publication. Concept and design were primarily contributed by A. Advani, with assistance from Patel. Data collection was primarily performed by Whitty, with assistance from Patel, and data interpretation was done by Patel and Pichardo. The manuscript was jointly written by Patel, Pichardo, Whitty, and S. Advani, with revision by A. Advani. 270 Journal of Managed Care & Specialty Pharmacy JMCP March 2014 References 1. World Health Organization. HIV/AIDS. Available at: http://www.who.int/ hiv/en/. Accessed October 29, 2013. 2. Schneider MF, Gange SJ, Williams CM, et al. Patterns of the hazard of death after AIDS through the evolution of antiretroviral therapy: 1984-2004. AIDS. 2005;19(17):2009-18. 3. Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services. 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